Nothing Special   »   [go: up one dir, main page]

US9433628B2 - Enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives - Google Patents

Enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives Download PDF

Info

Publication number
US9433628B2
US9433628B2 US14/073,928 US201314073928A US9433628B2 US 9433628 B2 US9433628 B2 US 9433628B2 US 201314073928 A US201314073928 A US 201314073928A US 9433628 B2 US9433628 B2 US 9433628B2
Authority
US
United States
Prior art keywords
cortexolone
propionate
crystalline form
composition
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US14/073,928
Other versions
US20140179654A1 (en
Inventor
Mauro Ajani
Luigi Moro
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cassiopea SpA
Original Assignee
Cassiopea SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40278805&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US9433628(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Cassiopea SpA filed Critical Cassiopea SpA
Priority to US14/073,928 priority Critical patent/US9433628B2/en
Assigned to COSMO DERMATOS SRL. reassignment COSMO DERMATOS SRL. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COSMO S.P.A.
Publication of US20140179654A1 publication Critical patent/US20140179654A1/en
Assigned to CASSIOPEA S.P.A. reassignment CASSIOPEA S.P.A. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: COSMO DERMATOS SRL
Priority to US14/886,774 priority patent/US9486458B2/en
Priority to US15/211,094 priority patent/US10159682B2/en
Priority to US15/211,087 priority patent/US10166245B2/en
Publication of US9433628B2 publication Critical patent/US9433628B2/en
Application granted granted Critical
Assigned to COSMO S.P.A. reassignment COSMO S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AJANI, MAURO, MORO, LUIGI
Priority to US16/195,083 priority patent/US10716796B2/en
Priority to US16/686,738 priority patent/US11207332B2/en
Priority to US17/455,538 priority patent/US11938141B2/en
Priority to US18/057,031 priority patent/US20230104965A1/en
Assigned to CASSIOPEA S.P.A. reassignment CASSIOPEA S.P.A. CHANGE OF ADDRESS Assignors: CASSIOPEA S.P.A.
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P33/00—Preparation of steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P33/00—Preparation of steroids
    • C12P33/005—Degradation of the lateral chains at position 17

Definitions

  • Cortexolone derivatives in which the hydroxyl group at position C-17 ⁇ is esterified with short chain aliphatic or aromatic acids, and the derivatives of the corresponding 9,11-dehydro derivative, are known to have an antiandrogenic effect.
  • EP1421099 describes cortexolone 17 ⁇ -propionate and 9,11-dehydro-cortexolone-17- ⁇ -butanoate regarding a high antiandrogenic biological activity demonstrated both “in vitro” and “in vivo” on the animal.
  • a method for obtaining the above mentioned derivatives is described by Gardi et al. (Gazz. Chim. It. 63, 43 1, 1963) and in U.S. Pat. No. 3,152,154 providing for the transformation of cortexolone, or transformation of 9,11-dehydrocortexolone, in the intermediate orthoester using orthoesters available in the market as a mixture of aprotic solvents such as cyclohexane and DMF, in presence of acid catalysis (ex. PTSA.H 2 O).
  • the intermediate orthoester thus obtained can be used as is or upon purification by suspension in a solvent capable of solubilizing impurities, preferably in alcohols.
  • the subsequent hydrolysis in a hydroalcoholic solution, buffered to pH 4-5 preferably in acetate buffer provides the desired monoester.
  • U.S. Pat. No. 3,152,154 describes how the hydrolysis of the diester in a basic environment is not convenient due to the formation of a mixture of 17 ⁇ ,21-diol, of 17- and 21-monoesters, alongside the initial non-reacted product.
  • an alcoholysis reaction using a lipase from Candida as a biocatalyst can be usefully applied during the preparation of 17 ⁇ monoesters of cortexolone, or its 9,11-dehydroderivatives.
  • the chemoselectivity of the special enzymatic reaction in alcoholysis conditions opens new perspectives for preparation, at industrial level with higher yields, of 17 ⁇ -monoesters with respect to the methods already indicated in literature.
  • the diesters serving as a substrate for the reaction of the invention can be prepared according to the prior art, for example following the one described in B. Turner, (Journal of American Chemical Society, 75, 3489, 1953) which provides for the esterification of corticosteroids with a linear carboxylic acid in presence of its anhydride and PTSA monohydrate.
  • an object of the present invention is a process for the preparation of 17 ⁇ monoesters of cortexolone, and its 9,11-dehydroderivatives, of formula I.
  • R is a linear or branched aliphatic or aromatic chain containing 1 to 10 carbon atoms, characterized in that a compound of formula II
  • FIG. 1 shows a DRX spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 2 shows a DSC spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 3 shows an IR spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 4 shows a DRX spectrum of crystalline form II of cortexolone-17 ⁇ -propionate.
  • FIG. 5 shows a DSC spectrum of crystalline form II of cortexolone-17 ⁇ -propionate.
  • FIG. 6 shows an IR spectrum of crystalline form II of cortexolone-17 ⁇ -propionate.
  • FIG. 7 shows a DRX spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 8 shows a DSC spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 9 shows an IR spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 10 shows a DRX spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 11 shows a DSC spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 12 shows an IR spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 13 shows a DRX spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 14 shows a DSC spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 15 shows an IR spectrum of crystalline form III of cortexolone-17 ⁇ -propionate.
  • FIG. 16 shows a DRX spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 17 shows a DSC spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 18 shows an IR spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 19 shows a DRX spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 20 shows a DSC spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 21 shows an IR spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 22 shows a DRX spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 23 shows a DSC spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 24 shows an IR spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 25 shows a DRX spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 26 shows a DSC spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 27 shows an IR spectrum of crystalline form I of cortexolone-17 ⁇ -propionate.
  • FIG. 28 shows a DRX spectrum of cortexolone-17 ⁇ -propionate crystallized during the preparation of a cream formulation.
  • the lipase from Candida used to catalyze the process of the present invention is preferably selected between the lipase from Candida cylindracea (CCL) and lipase from Candida antarctica of type B (CALB).
  • Lipase from Candida and in particular the ones from Candida cylindracea and Candida antarctica are proved to be capable of selectively hydrolyzing the ester function in position 21, contrary to the porcine pancreatic lipase (PPL) and to one from Pseudomonas fluorescens (PFL), which are proved to be almost inactive.
  • PPL porcine pancreatic lipase
  • PFL Pseudomonas fluorescens
  • the amount of said enzyme, calculated with respect to the initial substrate, may vary depending on the type of enzyme used.
  • said enzyme is preferably used in an amount in the range of 100 to 1,000,000 U/mmol; more preferably in the range of 1,000 to 1,000,000 U/mmol in case of CCL and in the range of 100 to 100,000 U/mmol in case of CALB. Even more preferably, said enzyme is present at an amount of about 60,000 U/mmol in case of CCL and about 5,000 U/mmol in case CALB.
  • the concentration of the initial diesters of formula II is preferably in the range of about 0.01 to 0.15 molar, more preferably about 0.025 molar.
  • the process of the invention preferably occurs in the presence of an organic solvent, more preferably an aprotic organic solvent.
  • Said solvent is then preferably selected from among toluene, acetonitrile, tetrahydrofuran, dichloromethane and/or chloroform.
  • the R′OH alcohol according to the invention is preferably selected from among methanol, ethanol, butanol and/or octanol.
  • Said alcohol is preferably present at a quantity in the range of about 0.5 to about 50 moles per mole of initial substrate, more preferably 5 moles per mole of substrate.
  • the process according to the present invention preferably occurs under constant stirring until the initial diester of formula II is dissolved. Subsequently the enzyme used is removed for filtration, preferably filtration on Celite and the monoester of formula I is obtained through evaporation of the solvent under low pressure.
  • the reaction time of the process is usually in the range of 20 to 150 hours, preferably in the range of 24 to 72 hours and the reaction temperature is preferably in the range of about 10 to 48° C., more preferably in the range of 20 to 32° C.
  • Table I summarizes the reaction conditions and the results of the enzymatic alcoholysis according to the present invention.
  • the enzymatic method according to the present invention also proved useful not only for converting 17 ⁇ -21-diesters of cortexolone or of 9,11-dehydro-cortexolone: in particular the 17 ⁇ -butanoate of 9,11-dehydrocortexolone was obtained starting from the corresponding dibutanoate preferably using the CCL enzyme and methanol as an acceptor alcohol of the acyl group.
  • the concentration of the initial 9,11-dehydro derivatives is preferably in the range of 0.01 to 0.15 molar, more preferably 0.025 molar.
  • reaction time is preferably in the range of 45 to 55 hours, preferably 53 hours.
  • reaction temperature is preferably in the range of 10 to 48° C., more preferably in the range of 20 to 32° C.
  • Table 2 shows the reaction conditions of the enzymatic alcoholysis of 17 ⁇ ,21-dibutanoate of 9,11-dehydrocortexolone and the related final yield of the respective monoester.
  • the process according to the present invention may optionally comprise a final step of crystallization from an organic solvent, water, buffered aqueous solutions and/or or their mixture.
  • the organic solvent of said step of crystallization is preferably selected from among diisopropylether, tert-butylmethylether, dichloromethane, ethyl acetate, hexane, acetone, ethanol, water or their mixture at any proportion.
  • an object of the present invention are the crystalline forms of cortexolone 17 ⁇ -propionate and of 9,11-cortexolone-17 ⁇ -butanoate.
  • the crystalline form I of 17 ⁇ -propionate is preferably obtained through crystallization from tert-butylmethylether.
  • concentration of 17 ⁇ -propionate in said solvent is in the range of 0.9 to 1.1 g in 9-11 ml of tert-butylmethylether preferably 1 g in 10 ml.
  • Said crystalline form I is characterized by a melting point in the range of about 133 to 135° C. and/or a DRX as in FIG. 1 and/or a DSC as shown in FIG. 2 and/or an IR as shown in FIG. 3 .
  • the crystalline form II of 17 ⁇ -propionate is preferably obtained through crystallization from diisopropylether.
  • concentration in said solvent is preferably in the range of 0.9 to 1.1 g in 54-66 ml of diisopropylether.
  • Said crystalline form II is characterized by a melting point in the range of about 114 to 116° C. and/or a DRX as in FIG. 4 and/or a DSC as shown in FIG. 5 and/or an IR as shown in FIG. 6 .
  • the crystalline form III of 17 ⁇ -propionate is preferably obtained through crystallization from a mixture of dichloromethane/n-hexane preferably in a ratio of about 1/30, acetone/n-hexane preferably in a ratio of about 1/8, or ethanol/water mixture preferably in a ratio of about 1/2.
  • the crystalline form III obtained from dichloromethane/n-hexane has a DRX as shown in FIG. 7 and/or a DSC as shown in FIG. 8 and/or an IR as shown in FIG. 9 .
  • the crystalline form III obtained from acetone/n-hexane has a DRX as shown in FIG. 10 and/or a DSC as shown in FIG. 11 and/or an IR as shown in FIG. 12 .
  • the crystalline form III obtained from ethanol/water has a DRX as shown in FIG. 13 and/or a DSC as shown in FIG. 14 and/or an IR as shown in FIG. 15 .
  • the crystalline form I of 9,11-dehydro-17 ⁇ -cortexolone is preferably obtained from tert-butylmethylether, diisopropylether, a dichloromethane/n-hexane mixture preferably in a ratio of 1/15, or an acetone/n-hexane mixture preferably in a ratio of 1/5.
  • the crystalline form I obtained from tert-butylmethylether has a DRX as shown in FIG. 16 and/or a DSC as shown in FIG. 17 and/or an IR as shown in FIG. 18 .
  • the crystalline form I obtained from diisopropylether has a DRX as shown in FIG. 19 and/or a DSC as shown in FIG. 20 and/or an IR as shown in FIG. 21 .
  • the crystalline form I obtained from dichloromethane/n-hexane has a DRX as shown in FIG. 22 and/or a DSC as shown in FIG. 23 and/or an IR as shown in FIG. 24 .
  • the crystalline form I obtained from acetone/n-hexane has a DRX as shown in FIG. 25 and/or a DSC as shown in FIG. 26 and/or an IR as shown in FIG. 27 .
  • Table 3 shows some identification parameters and conditions for obtaining the abovementioned crystalline forms.
  • FIG. dehydro form I butylmethylether 16 ( ⁇ H 62.63 J/g) 18 17 ⁇ - FIG. 17 cortexolone Crystalline diisopropylether 1 g/96 ml 136 FIG. 136.76° C.
  • FIG. form I 19 ( ⁇ H 60.48 J/g) 21
  • FIG. 20 Crystalline Dichloromethane/ 1 g/16 ml n.d.
  • FIG. form I n-hexane (dichloromethane/ 22 ( ⁇ H 66.66 J/g) 24 n-hexane FIG. 23 1/15) Crystalline Acetone/n- 1 g/21 ml n.d.
  • FIG. form I hexane (acetone/n- 25 ( ⁇ H 67.64 J/g) 27 hexane 1/5)
  • the solvate crystalline form IV of 17 ⁇ -propionate is preferably obtained through crystallization from an organic/water solvent mixture in a ratio generally in the range of 1/2 to 2/1, preferably from propylene glycol/water in a ratio of 1/1 or polyethylenglycol/water in a ratio of 1/1.
  • the crystallization of 17 ⁇ -propionate in solvate form may occur during the formulation processes of the final pharmaceutical form, where the manufacturing process of the pharmaceutical form provides for the dissolution of the active ingredient in an organic solvent, such as for example, propylene glycol, polyethylene glycol or short-chained aliphatic alcohols, followed by the addition of water in a ratio of 1/3 to 3/1 with respect to the organic solvents used for the dissolution of the active ingredient.
  • an organic solvent such as for example, propylene glycol, polyethylene glycol or short-chained aliphatic alcohols
  • an object of the present invention is a pharmaceutical composition containing at least one of the crystalline forms described above in association with at least one physiologically acceptable excipient.
  • compositions of the present invention can be of solid, semi-solid, pasty or liquid form and they are preferably selected from among tablets, capsules, powders, pellets, suspensions, emulsions, solutions, creams, gel, ointment, lotions or pastes both ready to use or to be reconstituted before use.
  • object of the present invention is the use, preferably for human beings, of at least one of the crystalline forms and/or solvates described above for the preparation of a medication for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or the cutaneous appendages.
  • an object of the present invention is the use of a liquid or semi-liquid formulation for topical administration, such as for example, cream, gel, ointment, emulsion or dispersion containing cortexolone-17 ⁇ -propionate in the range of 0.1 to 2% by weight, preferably in the range of 0.2 to 1%, in a crystalline form selected from among solvate forms I, II, III or IV, preferably in solvate form IV, both in solution and crystalline dispersion states, the latter being possibly obtained also in an extemporaneous manner by precipitation of the crystalline active ingredient upon addition of water or aqueous solution to a solution containing the same active ingredient in an organic solvent or a mixture of organic solvents, for the preparation of a medication for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or or skin appendages.
  • a liquid or semi-liquid formulation for topical administration such as for example, cream, gel, ointment, emulsion or disper
  • an object of the present invention is the use of a liquid or solid formulation for oral or systemic administration, such as for example, a tablet, capsule, granule or powder containing 9,11-dehydro-cortexolone-17 ⁇ -butanoate in the dosage in the range of 4 to 65% by weight, preferably in the range of 5 to 50%, with respect to the total formulation when said total formulation has a final weight of 200 mg or in the range of 1 to 25% by weight, preferably in the range of 2 to 20%, when the total formulation has a final weight of 500 mg in a crystalline form selected between solvate forms I, or IV, for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or or skin appendages.
  • a liquid or solid formulation for oral or systemic administration such as for example, a tablet, capsule, granule or powder containing 9,11-dehydro-cortexolone-17 ⁇ -butanoate in the dosage in the range of 4 to 65% by weight, preferably in
  • Said pathologies according to the invention are preferably selected from among acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, male contraception, polycystic ovary syndrome, control of aggressive or aberrant sexual behaviors and syndrome of precocious puberty.
  • the cream contains a dispersed crystalline fraction, made up of an active ingredient in solvate crystalline form IV, formed due to the precipitation of the active ingredient itself from the glycolic solution which contained it when the latter was added to the predominantly aqueous formulation.
  • the DRX spectra of the crystalline form present in the cream are indicated in FIG. 28 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Biochemistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)

Abstract

The present invention refers to a new enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives starting from the corresponding 17α,21-diesters which comprises an enzymatic alcoholysis reaction.
Furthermore, the present invention refers to new crystalline forms of cortexolone 17α-propionate and 9,11-dehydro-cortexolone 17α-butanoate.

Description

Cortexolone derivatives in which the hydroxyl group at position C-17α is esterified with short chain aliphatic or aromatic acids, and the derivatives of the corresponding 9,11-dehydro derivative, are known to have an antiandrogenic effect.
EP1421099 describes cortexolone 17α-propionate and 9,11-dehydro-cortexolone-17-α-butanoate regarding a high antiandrogenic biological activity demonstrated both “in vitro” and “in vivo” on the animal.
A method for obtaining the above mentioned derivatives is described by Gardi et al. (Gazz. Chim. It. 63, 43 1, 1963) and in U.S. Pat. No. 3,152,154 providing for the transformation of cortexolone, or transformation of 9,11-dehydrocortexolone, in the intermediate orthoester using orthoesters available in the market as a mixture of aprotic solvents such as cyclohexane and DMF, in presence of acid catalysis (ex. PTSA.H2O). The intermediate orthoester thus obtained can be used as is or upon purification by suspension in a solvent capable of solubilizing impurities, preferably in alcohols. The subsequent hydrolysis in a hydroalcoholic solution, buffered to pH 4-5 preferably in acetate buffer, provides the desired monoester.
Such synthesis is indicated in the diagram 1 below.
Figure US09433628-20160906-C00001
However, the monoesters thus obtained were, in the reaction conditions, unstable and, consequently hard to manipulate and isolate (R. Gardi et at Tetrahedron Letters, 448, 1961). The instability is above all due to the secondary reaction of migration of the esterifying acyl group from position 17 to position 21.
It is thus known that in order to obtain the above mentioned monoesters with a chemical purity in such a manner to be able to proceed to the biological tests, it is necessary to use, at the end of the synthesis, a purification process which is generally performed by means of column chromatography.
Furthermore, U.S. Pat. No. 3,152,154 describes how the hydrolysis of the diester in a basic environment is not convenient due to the formation of a mixture of 17α,21-diol, of 17- and 21-monoesters, alongside the initial non-reacted product.
Now, it has been surprisingly discovered that an alcoholysis reaction using a lipase from Candida as a biocatalyst can be usefully applied during the preparation of 17α monoesters of cortexolone, or its 9,11-dehydroderivatives.
As a matter of fact, it has been discovered that such enzymatic alcoholysis of the 17,21-diester of the cortexolone, or of its derivative 9,11-dehydro, selectively occurs in position 21 moving to the corresponding monoester in position 17, as shown in diagram 2 below:
Figure US09433628-20160906-C00002
The chemoselectivity of the special enzymatic reaction in alcoholysis conditions, according to the present invention, opens new perspectives for preparation, at industrial level with higher yields, of 17α-monoesters with respect to the methods already indicated in literature.
The diesters serving as a substrate for the reaction of the invention can be prepared according to the prior art, for example following the one described in B. Turner, (Journal of American Chemical Society, 75, 3489, 1953) which provides for the esterification of corticosteroids with a linear carboxylic acid in presence of its anhydride and PTSA monohydrate.
Therefore, an object of the present invention is a process for the preparation of 17α monoesters of cortexolone, and its 9,11-dehydroderivatives, of formula I.
Figure US09433628-20160906-C00003
wherein R is a linear or branched aliphatic or aromatic chain containing 1 to 10 carbon atoms, characterized in that a compound of formula II
Figure US09433628-20160906-C00004
    • wherein R bears the same meaning indicated above,
    • is reacted with a compound having the formula R′OH, wherein R′ is a linear chain containing 1 to 10 carbon atoms, preferably a C1-C8 alkyl, in presence of a lipase from Candida. According to the present invention R is preferably a C1-C4 alkyl, even more preferably it is selected from among CH3, CH3CH2, CH3(CH2)2 or CH3(CH2)3.
The dashed symbol in position 9,11 inside the abovementioned formulas I and II means that the double bond can be present (9,11-dehydroderivative) or not present in such position, as shown in the formulas indicated hereinafter
Figure US09433628-20160906-C00005
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a DRX spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 2 shows a DSC spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 3 shows an IR spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 4 shows a DRX spectrum of crystalline form II of cortexolone-17α-propionate.
FIG. 5 shows a DSC spectrum of crystalline form II of cortexolone-17α-propionate.
FIG. 6 shows an IR spectrum of crystalline form II of cortexolone-17α-propionate.
FIG. 7 shows a DRX spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 8 shows a DSC spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 9 shows an IR spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 10 shows a DRX spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 11 shows a DSC spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 12 shows an IR spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 13 shows a DRX spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 14 shows a DSC spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 15 shows an IR spectrum of crystalline form III of cortexolone-17α-propionate.
FIG. 16 shows a DRX spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 17 shows a DSC spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 18 shows an IR spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 19 shows a DRX spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 20 shows a DSC spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 21 shows an IR spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 22 shows a DRX spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 23 shows a DSC spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 24 shows an IR spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 25 shows a DRX spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 26 shows a DSC spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 27 shows an IR spectrum of crystalline form I of cortexolone-17α-propionate.
FIG. 28 shows a DRX spectrum of cortexolone-17α-propionate crystallized during the preparation of a cream formulation.
The lipase from Candida used to catalyze the process of the present invention is preferably selected between the lipase from Candida cylindracea (CCL) and lipase from Candida antarctica of type B (CALB).
Lipase from Candida, and in particular the ones from Candida cylindracea and Candida antarctica are proved to be capable of selectively hydrolyzing the ester function in position 21, contrary to the porcine pancreatic lipase (PPL) and to one from Pseudomonas fluorescens (PFL), which are proved to be almost inactive.
The amount of said enzyme, calculated with respect to the initial substrate, may vary depending on the type of enzyme used. In particular, said enzyme is preferably used in an amount in the range of 100 to 1,000,000 U/mmol; more preferably in the range of 1,000 to 1,000,000 U/mmol in case of CCL and in the range of 100 to 100,000 U/mmol in case of CALB. Even more preferably, said enzyme is present at an amount of about 60,000 U/mmol in case of CCL and about 5,000 U/mmol in case CALB.
Furthermore, from an economical/industrial point of view, the possibility to reutilize such enzymes in several cycles without losing the catalytic activity was proved.
The concentration of the initial diesters of formula II is preferably in the range of about 0.01 to 0.15 molar, more preferably about 0.025 molar.
The process of the invention preferably occurs in the presence of an organic solvent, more preferably an aprotic organic solvent.
Said solvent is then preferably selected from among toluene, acetonitrile, tetrahydrofuran, dichloromethane and/or chloroform.
The R′OH alcohol according to the invention is preferably selected from among methanol, ethanol, butanol and/or octanol.
Said alcohol is preferably present at a quantity in the range of about 0.5 to about 50 moles per mole of initial substrate, more preferably 5 moles per mole of substrate.
The process according to the present invention preferably occurs under constant stirring until the initial diester of formula II is dissolved. Subsequently the enzyme used is removed for filtration, preferably filtration on Celite and the monoester of formula I is obtained through evaporation of the solvent under low pressure.
When the compound of formula II is a 17α,21-diester of cortexolone, the reaction time of the process is usually in the range of 20 to 150 hours, preferably in the range of 24 to 72 hours and the reaction temperature is preferably in the range of about 10 to 48° C., more preferably in the range of 20 to 32° C.
Table I below summarizes the reaction conditions and the results of the enzymatic alcoholysis according to the present invention.
TABLE I
Enzymatic alcoholysis reaction of 17α,21-diesters of cortexolone
to produce the corresponding 17α-monoester.
Compound of Reaction Yield of
formula II time the monoester of
(diester) Enzyme Alcohol Solvent (hours) formula I*
Diacetate CCL Octanol Toluene 51 97%
CALB Ethanol Toluene 96 67%
CALB Octanol Acetonitrile 51 88%
Dipropionate CCL Ethanol Toluene 120 73%
CCL Butanol Toluene 24 100%
CCL Octanol Toluene 28 100%
CCL Butanol Acetonitrile 96 91%
CCL Butanol Tetrahydrofuran 96 86%
CCL Butanol Chloroform 96 10%
PPL Octanol Toluene 120 13%
PFL Methanol Chloroform 24 0%
CALB Octanol acetonitrile 76 91%
Dibutanoate CCL Toluene Butanol 74 98%
CCL Toluene Octanol 24 98%
Divalerate CCL Toluene Butanol 74 81%
CCL Toluene Octanol 48% 97%
*the conversion percentages were evaluated from the 1H-NMR spectra from the integrations of signals due to the hydrogens in position 21 of the corresponding diesters and monoesters.
The enzymatic method according to the present invention also proved useful not only for converting 17α-21-diesters of cortexolone or of 9,11-dehydro-cortexolone: in particular the 17α-butanoate of 9,11-dehydrocortexolone was obtained starting from the corresponding dibutanoate preferably using the CCL enzyme and methanol as an acceptor alcohol of the acyl group.
The concentration of the initial 9,11-dehydro derivatives is preferably in the range of 0.01 to 0.15 molar, more preferably 0.025 molar.
In this case, the reaction time is preferably in the range of 45 to 55 hours, preferably 53 hours.
Also in this case the reaction temperature is preferably in the range of 10 to 48° C., more preferably in the range of 20 to 32° C.
Table 2 below shows the reaction conditions of the enzymatic alcoholysis of 17α,21-dibutanoate of 9,11-dehydrocortexolone and the related final yield of the respective monoester.
TABLE 2
Enzymatic alcoholysis reaction of I7α,21-diesters of 9,11-dehydro-
cortexolone to produce the corresponding 17α-monoester.
Compound Reaction Yield in
of formula II time compound of
(diester) Enzyme Alcohol Solvent (hours) formula I*
Dibutanoate CCL Methanol Toluene 53 79%
Dibutanoate CCL Ethanol Toluene 53 28%
Dibutanoate CCL Butanol Toluene 53 100%
Dibutanoate CCL Octanol Toluene 53 100%
*the conversion percentages were evaluated from the 1H-NMR spectra from the integrations of signals due to the hydrogens in position 21 of the corresponding diesters and monoesters.
Furthermore, the process according to the present invention may optionally comprise a final step of crystallization from an organic solvent, water, buffered aqueous solutions and/or or their mixture.
The organic solvent of said step of crystallization is preferably selected from among diisopropylether, tert-butylmethylether, dichloromethane, ethyl acetate, hexane, acetone, ethanol, water or their mixture at any proportion.
Thus, further object of the present invention are crystalline forms of 17α-monoesters of cortexolone, and their corresponding 9,11-dehydro derivatives.
In particular, an object of the present invention are the crystalline forms of cortexolone 17α-propionate and of 9,11-cortexolone-17α-butanoate.
The crystalline form I of 17α-propionate is preferably obtained through crystallization from tert-butylmethylether. The concentration of 17α-propionate in said solvent is in the range of 0.9 to 1.1 g in 9-11 ml of tert-butylmethylether preferably 1 g in 10 ml. Said crystalline form I is characterized by a melting point in the range of about 133 to 135° C. and/or a DRX as in FIG. 1 and/or a DSC as shown in FIG. 2 and/or an IR as shown in FIG. 3.
The crystalline form II of 17α-propionate is preferably obtained through crystallization from diisopropylether. The concentration in said solvent is preferably in the range of 0.9 to 1.1 g in 54-66 ml of diisopropylether.
Said crystalline form II is characterized by a melting point in the range of about 114 to 116° C. and/or a DRX as in FIG. 4 and/or a DSC as shown in FIG. 5 and/or an IR as shown in FIG. 6.
The crystalline form III of 17α-propionate is preferably obtained through crystallization from a mixture of dichloromethane/n-hexane preferably in a ratio of about 1/30, acetone/n-hexane preferably in a ratio of about 1/8, or ethanol/water mixture preferably in a ratio of about 1/2.
The melting point of said crystalline forms III could not be determined.
The crystalline form III obtained from dichloromethane/n-hexane has a DRX as shown in FIG. 7 and/or a DSC as shown in FIG. 8 and/or an IR as shown in FIG. 9. The crystalline form III obtained from acetone/n-hexane has a DRX as shown in FIG. 10 and/or a DSC as shown in FIG. 11 and/or an IR as shown in FIG. 12.
The crystalline form III obtained from ethanol/water has a DRX as shown in FIG. 13 and/or a DSC as shown in FIG. 14 and/or an IR as shown in FIG. 15.
The crystalline form I of 9,11-dehydro-17α-cortexolone is preferably obtained from tert-butylmethylether, diisopropylether, a dichloromethane/n-hexane mixture preferably in a ratio of 1/15, or an acetone/n-hexane mixture preferably in a ratio of 1/5.
The crystalline form I obtained from tert-butylmethylether has a DRX as shown in FIG. 16 and/or a DSC as shown in FIG. 17 and/or an IR as shown in FIG. 18.
The crystalline form I obtained from diisopropylether has a DRX as shown in FIG. 19 and/or a DSC as shown in FIG. 20 and/or an IR as shown in FIG. 21.
The crystalline form I obtained from dichloromethane/n-hexane has a DRX as shown in FIG. 22 and/or a DSC as shown in FIG. 23 and/or an IR as shown in FIG. 24.
The crystalline form I obtained from acetone/n-hexane has a DRX as shown in FIG. 25 and/or a DSC as shown in FIG. 26 and/or an IR as shown in FIG. 27.
The differences observable in the DRX diagrams regarding the form III of 17α-propionate and regarding the form I of 9,11-dehydro derivative are to be deemed irrelevant in that they are due to the phenomena of crystal disorientation. Likewise, the differences observed in IR and DSC are to be deemed irrelevant in that they are due to variations when preparing the sample and/or when performing the analysis.
Table 3 shows some identification parameters and conditions for obtaining the abovementioned crystalline forms.
TABLE 3
Concentrations
Compound (g Melting
of formula I Solid compound/ml point
(monoester) form Solvents solvent) (° C.) DRX DSC IR
Cortexolone Crystalline Tert- 1 g/10 ml 133-135 FIG. 1 134.90° C. FIG. 3
17α- form I butylmethylether (ΔH = 40.68 J/g)
propionate FIG. 2
Crystalline diisopropylether 1 g/60 ml 114-116 FIG. 4 115.85° C. FIG. 6
form (ΔH = 46.61 J/g)
II FIG. 5
Crystalline dichloromethane/ 1 g/15.51 ml n.d. FIG. 7 134.90° C. FIG. 9
form n-hexane (dichloromethane/ (ΔH = 42.45 J/g)
III n-hexane FIG. 8
1/30)
Crystalline Acetone/n- 1 g/9 ml n.d. FIG. 134.18° C. FIG.
form hexane (acetone/n- 10 (ΔH = 43.83 J/g) 12
III hexane 1/8) FIG. 11
Crystalline Ethanol/water 1 g/24 ml n.d FIG. 134.29° C. FIG.
form (ethanol/water 13 (ΔH = 43.34 J/g) 15
III 1/2) FIG. 14
9,11- Crystalline Tert- 1 g/24 ml n.d. FIG. 137.45° C. FIG.
dehydro form I butylmethylether 16 (ΔH = 62.63 J/g) 18
17α- FIG. 17
cortexolone
Crystalline diisopropylether 1 g/96 ml 136 FIG. 136.76° C. FIG.
form I 19 (ΔH = 60.48 J/g) 21
FIG. 20
Crystalline Dichloromethane/ 1 g/16 ml n.d. FIG. 136.65° C. FIG.
form I n-hexane (dichloromethane/ 22 (ΔH = 66.66 J/g) 24
n-hexane FIG. 23
1/15)
Crystalline Acetone/n- 1 g/21 ml n.d. FIG. 136.49° C. FIG.
form I hexane (acetone/n- 25 (ΔH = 67.64 J/g) 27
hexane 1/5) FIG. 26
The existence of a pseudo polymorph crystalline form of 17α-propionate, characterized by the presence of a crystallization water molecule and defined as solvate form IV was determined.
The solvate crystalline form IV of 17α-propionate is preferably obtained through crystallization from an organic/water solvent mixture in a ratio generally in the range of 1/2 to 2/1, preferably from propylene glycol/water in a ratio of 1/1 or polyethylenglycol/water in a ratio of 1/1.
The crystallization of 17α-propionate in solvate form may occur during the formulation processes of the final pharmaceutical form, where the manufacturing process of the pharmaceutical form provides for the dissolution of the active ingredient in an organic solvent, such as for example, propylene glycol, polyethylene glycol or short-chained aliphatic alcohols, followed by the addition of water in a ratio of 1/3 to 3/1 with respect to the organic solvents used for the dissolution of the active ingredient.
Furthermore, an object of the present invention is a pharmaceutical composition containing at least one of the crystalline forms described above in association with at least one physiologically acceptable excipient.
The compositions of the present invention can be of solid, semi-solid, pasty or liquid form and they are preferably selected from among tablets, capsules, powders, pellets, suspensions, emulsions, solutions, creams, gel, ointment, lotions or pastes both ready to use or to be reconstituted before use.
Lastly, object of the present invention is the use, preferably for human beings, of at least one of the crystalline forms and/or solvates described above for the preparation of a medication for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or the cutaneous appendages.
In particular, an object of the present invention is the use of a liquid or semi-liquid formulation for topical administration, such as for example, cream, gel, ointment, emulsion or dispersion containing cortexolone-17α-propionate in the range of 0.1 to 2% by weight, preferably in the range of 0.2 to 1%, in a crystalline form selected from among solvate forms I, II, III or IV, preferably in solvate form IV, both in solution and crystalline dispersion states, the latter being possibly obtained also in an extemporaneous manner by precipitation of the crystalline active ingredient upon addition of water or aqueous solution to a solution containing the same active ingredient in an organic solvent or a mixture of organic solvents, for the preparation of a medication for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or or skin appendages.
Additionally, an object of the present invention is the use of a liquid or solid formulation for oral or systemic administration, such as for example, a tablet, capsule, granule or powder containing 9,11-dehydro-cortexolone-17α-butanoate in the dosage in the range of 4 to 65% by weight, preferably in the range of 5 to 50%, with respect to the total formulation when said total formulation has a final weight of 200 mg or in the range of 1 to 25% by weight, preferably in the range of 2 to 20%, when the total formulation has a final weight of 500 mg in a crystalline form selected between solvate forms I, or IV, for treating pathologies affecting the urogenital system, the endocrine system, the skin and/or or skin appendages.
Said pathologies according to the invention are preferably selected from among acne, seborrhoeic dermatitis, androgenetic alopecia, hirsutism, benign prostatic hyperplasia, forms of prostate cancer, male contraception, polycystic ovary syndrome, control of aggressive or aberrant sexual behaviors and syndrome of precocious puberty.
The following examples are included to enhance the understanding of the present invention without restricting it in any way whatsoever.
EXAMPLES Example 1 Alcoholysis with CCL of Cortexolone 17α,21-dipropionate
Add butanol (0.4 g, 5.45 mmoles) and CCL (17.4 g, 3.86 U/mg, FLUKA) to a solution of cortexolone-17α,21-dipropionate (0.5 g, 1.09 mmoles) in toluene (50 ml). Maintain the mixture under stirring, at 30° C., following the progress of the reaction in TLC (Toluene/ethyl acetate 6/4) until the initial material is dissolved (24 h). Remove the enzyme by means of filtration using a Celite layer. Recover the cortexolone 17α-propionate (0.437, 99%) after evaporation under low pressure. Through crystallization from diisopropyl ether you obtain a product with a purity >99% in HPLC.
1H-NMR (500 MHz, CDCl3) relevant signals δ (ppm) 5.78 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.25 (dd, 1H, H-21), 1.22 (s, 3H, CH3-19), 1.17 (t, 3H, CH3), 0.72 (s, 3H, CH3-18). P.f. 114° C.
Example 2
According to the method described in example 1 prepare cortexolone-17α-butanoate.
IH-NMR relevant signals δ (ppm) 5.78 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.23 (s, 3H, CH3-19), 0.97 (t, 3H, CH3), 0.73 (s, 3H, CH3-18). P.F. 134-136° C.
Example 3
According to the method described in the example prepare cortexolone-17α-valerate.
1H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.22 (s, 3H, CH3-19), 0.95 (t, 3H, CH3), 0.72 (s, 3H, CH3-18). P.f 114° C. (diisopropyl ether).
Example 4
According to the method described in the example prepare 9,11-dehydro-cortexolone-17α-butanoate.
1H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 5.54 (m, 1H, H-9), 4.29 (dd, 1H, H-21), 4.24 (dd, 1H, H-21), 1.32 (s, 3H, CH3-19), 0.94 (t, 3H, CH3), 0.68 (s, 3H, CH3-18). P.f 135-136° C. (acetone/hexane).
Example 5 Alcoholysis with CALB of cortexolone-17α,21-dipropionate
Dissolve cortexolone, 17α, 2-dipropionate (0.5 g, 1.09 mmoles) in acetonitrile (40 ml), add CALB (2.3 g, 2.5 U/mg Fluka) and octanol (0.875 ml). Leave the mixture under stirring, at 30° C., for 76 hrs. Remove the enzyme by means of filtration using a paper filter. Once the solvents evaporate, recover a solid (0.4758) which upon analysis 1H-NMR shall appear made up of cortexolone-17α-propionate at 91%.
Example 6 Crystallization
Add the solvent (t-butylmethylether or diisopropylether) to the sample according to the ratios indicated in Table 3. Heat the mixture to the boiling temperature of the solvent, under stirring, until the sample dissolves completely. Cool to room temperature and leave it at this temperature, under stirring, for 6 hours. Filter using a buchner funnel and maintain the solid obtained, under low pressure, at a room temperature for 15 hours and then, at 40° C., for 5 hours.
Example 7 Precipitation
Dissolve the sample in the suitable solvent (dichloromethane, acetone, ethyl acetate or ethanol) according to the ratios indicated in table 3 and then add the solvent, hexane or water, according to the ratios indicated in table 3, maintaining the mixture, under stiffing, at room temperature. Recover the precipitate by filtration using a buchner funnel and desiccate as in example 6.
Example 8
Obtaining a pharmaceutical form containing the medication in a defined crystalline form.
Prepare a fluid cream containing 2% cetylic alcohol, 16% glyceryl monostearate, 10% vaseline oil, 13% propylene glycol, 10% polyethylenglycol with low polymerization 1.5% polysorbate 80 and 47.5% purified water. Add 1 g of cortexolone 17α-propionate of crystalline form III to 100 g of this cream and subject the mixture to homogenization by means of a turbine agitator until you obtain homogeneity. You obtain a cream containing a fraction of an active ingredient dissolved in the formulation vehicle and a non-dissolved fraction of an active ingredient, present as a crystal of crystalline form III. This preparation is suitable for use as a formulation vehicle for skin penetration tests on Franz cells, where a coefficient of penetration in the range of 0.04 to 0.03 cm/h is observed on the preparation.
Example 9 Obtaining the Pharmaceutical Form Containing the Medication in Solvate Form IV for Replacing the Solvent During the Galenic Formulation Procedure
Dissolve 100 g of cortexolone 17α-propionate of crystalline form III in 2500 g of propylene glycol under stirring at room temperature. Separately prepare, by using a turboemulsifier raising the temperature up to about 70° C., an emulsion with 250 g of Cetylic alcohol, 1500 g of glyceryl monostearate, 1000 g of liquid paraffin, 5 g of mixed tocopherols, 100 g of polysorbate 80 and 4650 g of water. After cooling the emulsion up to about 30° C., add—under stirring and under negative pressure—the cortexolone 17α-propionate solution in propylene glycol. Maintain the emulsioned cream under stifling until you obtain homogeneity, making sure the temperature remains low by means the circulation of a coolant.
The cream contains a dispersed crystalline fraction, made up of an active ingredient in solvate crystalline form IV, formed due to the precipitation of the active ingredient itself from the glycolic solution which contained it when the latter was added to the predominantly aqueous formulation. The DRX spectra of the crystalline form present in the cream are indicated in FIG. 28.

Claims (24)

What is claimed is:
1. Crystalline form IV of cortexolone-17α-propionate characterized by a DRX as shown in FIG. 28.
2. Crystalline form IV of cortexolone-17α-propionate characterized by XRPD peaks at about 4.8, 12.9, 14.4, 15.8, 16, 19.3, and 19.5 degrees 2theta.
3. A process for preparing crystalline form IV of cortexolone-17α-propionate, the process comprising crystallizing cortexolone-17α-propionate from a propylene glycol/water or polyethylene glycol/water mixture.
4. The process of claim 3, wherein the propylene glycol/water mixture has a ratio of propylene glycol to water of from about 1/2 to about 2/1.
5. The process of claim 4, wherein the ratio of propylene glycol to water is about 1/1.
6. The process of claim 3, wherein the polyethylene glycol/water mixture has a ratio of polyethylene glycol to water of from about 1/2 to about 2/1.
7. The process of claim 6, wherein the ratio of polyethylene glycol to water is about 1/1.
8. The process of claim 3, wherein the propylene glycol/water mixture has a ratio of propylene glycol to water of from about 1/3 to about 3/1.
9. Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 3.
10. Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 4.
11. Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 5.
12. Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 6.
13. Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 7.
14. A pharmaceutical composition comprising crystalline form IV of cortexolone-17α-propionate, water, and at least one physiologically acceptable excipient.
15. The composition of claim 14, wherein the at least one physiologically acceptable excipient is propylene glycol, cetylic alcohol, glyceryl monostearate, liquid paraffin, or a combination of any of the foregoing.
16. The composition of claim 14, further comprising mixed tocopherols, polysorbate 80, or a combination thereof.
17. The composition of claim 14, wherein the composition is in the form of a cream.
18. The composition of claim 14, wherein the composition further comprises solubilized cortexolone-17α-propionate.
19. The composition of claim 18, wherein the solubilized cortexolone-17α-propionate and crystalline form IV of cortexolone-17α-propionate together comprise 0.1 to 2% by weight of the composition.
20. The composition of claim 19, wherein the solubilized cortexolone-17α-propionate and crystalline form IV of cortexolone-17α-propionate together comprise 0.2 to 1% by weight of the composition.
21. The composition of claim 14, wherein the crystalline form IV of cortexolone-17α-propionate is present at from about 0.1 to about 2% by weight of the composition.
22. A pharmaceutical composition comprising crystalline form IV of cortexolone-17α-propionate.
23. The composition of claim 22, wherein the composition is in the form of a tablet, capsule, powder, pellet, suspension, emulsion, cream, gel, ointment, lotion, or paste.
24. The composition of claim 22, wherein the composition is in the form of a solid, semi-solid, or a paste.
US14/073,928 2007-08-03 2013-11-07 Enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives Active 2029-02-28 US9433628B2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US14/073,928 US9433628B2 (en) 2007-08-03 2013-11-07 Enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US14/886,774 US9486458B2 (en) 2007-08-03 2015-10-19 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US15/211,087 US10166245B2 (en) 2007-08-03 2016-07-15 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US15/211,094 US10159682B2 (en) 2007-08-03 2016-07-15 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US16/195,083 US10716796B2 (en) 2007-08-03 2018-11-19 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US16/686,738 US11207332B2 (en) 2007-08-03 2019-11-18 Enzymatic process for obtaining 17 α-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US17/455,538 US11938141B2 (en) 2007-08-03 2021-11-18 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US18/057,031 US20230104965A1 (en) 2007-08-03 2022-11-18 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
ITMI2007A001616 2007-08-03
IT001616A ITMI20071616A1 (en) 2007-08-03 2007-08-03 ENZYMATIC PROCESS FOR THE OBTAINING OF 17-ALFA MONOESTERS OF CORTEXOLONE AND / OR ITS 9,11-DEIDRODERIVATI.
ITMI2007A1616 2007-08-03
PCT/EP2008/059702 WO2009019138A2 (en) 2007-08-03 2008-07-24 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US67193210A 2010-08-12 2010-08-12
US14/073,928 US9433628B2 (en) 2007-08-03 2013-11-07 Enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US12/671,932 Division US8785427B2 (en) 2007-08-03 2008-07-24 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
PCT/EP2008/059702 Division WO2009019138A2 (en) 2007-08-03 2008-07-24 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US14/886,774 Division US9486458B2 (en) 2007-08-03 2015-10-19 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US15/211,087 Division US10166245B2 (en) 2007-08-03 2016-07-15 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US15/211,094 Division US10159682B2 (en) 2007-08-03 2016-07-15 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Publications (2)

Publication Number Publication Date
US20140179654A1 US20140179654A1 (en) 2014-06-26
US9433628B2 true US9433628B2 (en) 2016-09-06

Family

ID=40278805

Family Applications (9)

Application Number Title Priority Date Filing Date
US12/671,932 Active 2030-07-25 US8785427B2 (en) 2007-08-03 2008-07-24 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US14/073,928 Active 2029-02-28 US9433628B2 (en) 2007-08-03 2013-11-07 Enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US14/886,774 Active US9486458B2 (en) 2007-08-03 2015-10-19 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US15/211,087 Active 2028-08-27 US10166245B2 (en) 2007-08-03 2016-07-15 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US15/211,094 Active 2028-08-14 US10159682B2 (en) 2007-08-03 2016-07-15 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US16/195,083 Active US10716796B2 (en) 2007-08-03 2018-11-19 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US16/686,738 Active 2028-11-20 US11207332B2 (en) 2007-08-03 2019-11-18 Enzymatic process for obtaining 17 α-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US17/455,538 Active 2028-09-01 US11938141B2 (en) 2007-08-03 2021-11-18 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US18/057,031 Pending US20230104965A1 (en) 2007-08-03 2022-11-18 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US12/671,932 Active 2030-07-25 US8785427B2 (en) 2007-08-03 2008-07-24 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Family Applications After (7)

Application Number Title Priority Date Filing Date
US14/886,774 Active US9486458B2 (en) 2007-08-03 2015-10-19 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US15/211,087 Active 2028-08-27 US10166245B2 (en) 2007-08-03 2016-07-15 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US15/211,094 Active 2028-08-14 US10159682B2 (en) 2007-08-03 2016-07-15 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US16/195,083 Active US10716796B2 (en) 2007-08-03 2018-11-19 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US16/686,738 Active 2028-11-20 US11207332B2 (en) 2007-08-03 2019-11-18 Enzymatic process for obtaining 17 α-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US17/455,538 Active 2028-09-01 US11938141B2 (en) 2007-08-03 2021-11-18 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US18/057,031 Pending US20230104965A1 (en) 2007-08-03 2022-11-18 Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Country Status (25)

Country Link
US (9) US8785427B2 (en)
EP (5) EP2503005B1 (en)
JP (3) JP5646992B2 (en)
KR (1) KR101495192B1 (en)
CN (3) CN104861023B (en)
AR (3) AR072235A1 (en)
AU (1) AU2008285784B2 (en)
BR (1) BRPI0814163A2 (en)
CA (3) CA2691445C (en)
DK (4) DK2503004T3 (en)
ES (4) ES2554934T3 (en)
HR (4) HRP20140421T1 (en)
HU (3) HUE026507T2 (en)
IT (1) ITMI20071616A1 (en)
LT (1) LT2966175T (en)
MX (4) MX363701B (en)
NZ (3) NZ599437A (en)
PL (4) PL2173891T3 (en)
PT (4) PT2173891E (en)
RS (4) RS54354B1 (en)
RU (2) RU2482190C2 (en)
SI (4) SI2503005T1 (en)
TR (1) TR201909129T4 (en)
WO (1) WO2009019138A2 (en)
ZA (2) ZA201000587B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10159682B2 (en) 2007-08-03 2018-12-25 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20132157A1 (en) 2013-12-20 2015-06-21 Cosmo Dermatos Srl CORTEXOLONE 17ALFA-PROPIONATE FOR USE IN THE TREATMENT OF SKIN WOUNDS AND / OR ATROPHIC SKIN DISORDERS. 17ALFA CORTEXOLONE-PROPIONED FOR USE IN THE TREATMENT OF SKIN WOUNDS AND / OR ATROPHIC SKIN DISORDERS.
EP3006453A1 (en) * 2014-10-08 2016-04-13 Cosmo Technologies Ltd. 17alpha-monoesters and 17alpha,21-diesters of cortexolone for use in the treatment of tumors
EP3108879A1 (en) 2015-06-25 2016-12-28 Cassiopea S.p.A. High concentration formulation
CN112028956A (en) * 2020-09-10 2020-12-04 那路新 Method for synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione
ES2943573R1 (en) * 2020-10-19 2024-04-09 Ind Chimica Srl Process for the preparation of 21-(acetyloxy)-17-(1-oxopropoxy)-pregn-4-ene-3,20-dione
IT202100008429A1 (en) 2021-04-06 2022-10-06 Farmabios Spa Process for the preparation of cortexolone 17α-propionate and its new hydrated crystalline form
CN114410727B (en) * 2022-01-25 2023-09-19 山东诺明康药物研究院有限公司 Preparation method of clavulanone
CN115073546A (en) * 2022-06-01 2022-09-20 浙江神洲药业有限公司 Preparation method of novel androgen receptor inhibitor
CN115466301A (en) * 2022-08-29 2022-12-13 扬州奥锐特药业有限公司 Steroid compound, crystal form A thereof, and preparation method and application thereof
WO2024165502A1 (en) 2023-02-07 2024-08-15 Farmabios S.P.A. Cocrystals of cortexolone 17-propionate and methods for their preparation
WO2024208997A1 (en) 2023-04-07 2024-10-10 Cassiopea S.P.A. Clascoterone and minoxidil combination therapy for use in treating hair loss

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2985650A (en) 1958-05-28 1961-05-23 Syntex Sa 6alpha-ammonio-derivatives of 11-keto cortical hormones
US3152154A (en) 1961-06-24 1964-10-06 Vismara Francesco Spa 17-monoesters of 17alpha, 21-dihydroxy steroids and process for the preparation thereof
US3431173A (en) 1966-04-25 1969-03-04 Koninklijke Gist Spiritus Process for the preparation of 17alpha-acyloxy-21-hydroxy-pregnanes
US3530038A (en) 1966-04-25 1970-09-22 Koninklijke Gist Spiritus Process for preparation of trihydroxy steroids
US3780177A (en) 1967-06-16 1973-12-18 Warner Lambert Co 17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use
JPS5210489A (en) 1975-07-15 1977-01-26 Taisho Pharmaceut Co Ltd Preparation of 17-esters of pregnane steroids
JPS59106500A (en) 1982-11-22 1984-06-20 シエ−リング・アクチエンゲゼルシヤフト Novel 6 alpha-methylcorticoid, manufacture and medicine for skin disease therapy
JPS60161998A (en) 1984-01-20 1985-08-23 シエーリング・アクチエンゲゼルシヤフト 1 alpha,2 alpha-methylene-6-methylene- or 6 alpha-methyl-pregnene, manufacture and antiandrogenic for local effect of skin disease treatment
US5264428A (en) 1990-02-16 1993-11-23 Kanoldt Arzneimittel Gmbh Use of stigmasta-4-en-3-one in the treatment of androgen dependent diseases
EP0791771A1 (en) 1994-11-09 1997-08-27 Komatsu Ltd. Method of controlling speed change of hydraulic drive device for vehicle and speed change device
DE19653730A1 (en) 1996-12-11 1998-06-18 Schering Ag Immobilized proteins from crude extract and their use for the conversion of esters
WO2002094843A1 (en) 2001-05-22 2002-11-28 Pfizer Products Inc. Crystal forms of azithromycin
WO2003014141A1 (en) 2001-08-10 2003-02-20 Cosmo S.P.A. 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents
WO2003080042A1 (en) 2002-03-27 2003-10-02 Shionogi & Co., Ltd. Decomposition inhibitor for extracellular matrix of cartilage
WO2004014935A1 (en) 2002-08-02 2004-02-19 Schering Aktiengesellschaft Progesterone receptor modulators having an increased antigonadotropic activity for use in female fertility testing and hormone replacement therapy
WO2006121097A1 (en) 2005-05-12 2006-11-16 Astellas Pharma Inc. Bicyclic heterocyclic derivative or salt thereof
WO2007014927A2 (en) 2005-07-29 2007-02-08 Tibotec Pharmaceuticals Ltd. Macrocyclic inhibitors of hepatitis c virus
WO2007031349A1 (en) 2005-09-14 2007-03-22 Cosmo Bio-Technologies Srl Use of c3-c10 17alfa-esters of 9,11-dehydrocortexolone as anti-gonadotrophic agents.

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB791771A (en) 1954-07-29 1958-03-12 Merck & Co Inc Steroid compounds
US3733318A (en) 1972-03-23 1973-05-15 Syntex Corp 21-orthoesters of cortical steroids and methods of preparing same
GB2109817B (en) 1981-11-18 1985-07-03 Ibm Electrodeposition of chromium
US4920216A (en) 1987-05-28 1990-04-24 The Trustees Of Columbia In The City Of New York Selective chlorination of steroids and other substrates directed by covalently linked pyridine derivatives acting as templates
CA2263940A1 (en) 1997-06-25 1998-12-30 Teijin Limited Vitamin d3 derivatives and remedies for inflammatory respiratory diseases prepared from the same
WO2004060347A2 (en) 2002-09-03 2004-07-22 Transform Pharmaceuticals, Inc. Pharmaceutical propylene glycol solvate compositions
EP1539183A4 (en) 2002-08-28 2007-04-25 Hollis Eden Pharmaceuticals Therapeutic treatment methods
JP4425921B2 (en) 2003-03-05 2010-03-03 メルク フロスト カンパニー Nitrogen oxide releasing prodrug of diaryl 2- (5H) -furanone acting as cyclooxygenase-2 inhibitor
US20050008704A1 (en) 2003-07-11 2005-01-13 Ray Anup Kumar Pharmaceutical composition for solubility enhancement of hydrophobic drugs
ITMI20071616A1 (en) * 2007-08-03 2009-02-04 Cosmo Spa ENZYMATIC PROCESS FOR THE OBTAINING OF 17-ALFA MONOESTERS OF CORTEXOLONE AND / OR ITS 9,11-DEIDRODERIVATI.
EP3178465A1 (en) 2010-12-06 2017-06-14 Follica, Inc. Methods for treating baldness and promoting hair growth
ITMI20132157A1 (en) 2013-12-20 2015-06-21 Cosmo Dermatos Srl CORTEXOLONE 17ALFA-PROPIONATE FOR USE IN THE TREATMENT OF SKIN WOUNDS AND / OR ATROPHIC SKIN DISORDERS. 17ALFA CORTEXOLONE-PROPIONED FOR USE IN THE TREATMENT OF SKIN WOUNDS AND / OR ATROPHIC SKIN DISORDERS.
EP3108879A1 (en) 2015-06-25 2016-12-28 Cassiopea S.p.A. High concentration formulation

Patent Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2985650A (en) 1958-05-28 1961-05-23 Syntex Sa 6alpha-ammonio-derivatives of 11-keto cortical hormones
US3152154A (en) 1961-06-24 1964-10-06 Vismara Francesco Spa 17-monoesters of 17alpha, 21-dihydroxy steroids and process for the preparation thereof
US3431173A (en) 1966-04-25 1969-03-04 Koninklijke Gist Spiritus Process for the preparation of 17alpha-acyloxy-21-hydroxy-pregnanes
US3530038A (en) 1966-04-25 1970-09-22 Koninklijke Gist Spiritus Process for preparation of trihydroxy steroids
US3780177A (en) 1967-06-16 1973-12-18 Warner Lambert Co 17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use
JPS5210489A (en) 1975-07-15 1977-01-26 Taisho Pharmaceut Co Ltd Preparation of 17-esters of pregnane steroids
JPS59106500A (en) 1982-11-22 1984-06-20 シエ−リング・アクチエンゲゼルシヤフト Novel 6 alpha-methylcorticoid, manufacture and medicine for skin disease therapy
US4645763A (en) 1982-11-22 1987-02-24 Schering Aktiengesellschaft 6α-methyl corticoids, their production and use
JPS60161998A (en) 1984-01-20 1985-08-23 シエーリング・アクチエンゲゼルシヤフト 1 alpha,2 alpha-methylene-6-methylene- or 6 alpha-methyl-pregnene, manufacture and antiandrogenic for local effect of skin disease treatment
US4670427A (en) 1984-01-20 1987-06-02 Schering Aktiengesellschaft 1α,2α-methylene-6-methylene- and 6α-methylpregnenes, their preparation and pharmaceutical use
US5264428A (en) 1990-02-16 1993-11-23 Kanoldt Arzneimittel Gmbh Use of stigmasta-4-en-3-one in the treatment of androgen dependent diseases
EP0791771A1 (en) 1994-11-09 1997-08-27 Komatsu Ltd. Method of controlling speed change of hydraulic drive device for vehicle and speed change device
DE19653730A1 (en) 1996-12-11 1998-06-18 Schering Ag Immobilized proteins from crude extract and their use for the conversion of esters
AU729928B2 (en) 1996-12-11 2001-02-15 Schering Aktiengesellschaft Immobilized esterases from crude extract and their use
WO2002094843A1 (en) 2001-05-22 2002-11-28 Pfizer Products Inc. Crystal forms of azithromycin
JP2004530703A (en) 2001-05-22 2004-10-07 ファイザー・プロダクツ・インク Crystalline azithromycin
US20120149671A1 (en) 2001-08-10 2012-06-14 Cosmo Spa, 17alpha, 21-dihydroxypregnene esters as antiandrogenic agents
WO2003014141A1 (en) 2001-08-10 2003-02-20 Cosmo S.P.A. 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents
US20140154306A1 (en) 2001-08-10 2014-06-05 Cosmo S.P.A. 17alfa, 21-dihydroxypregnene esters as antiandrogenic agents
JP2005504762A (en) 2001-08-10 2005-02-17 コスモ・ソチエタ・ペル・アチオニ 17alpha, 21-dihydroxypregnene ester as an antiandrogenic drug
WO2003080042A1 (en) 2002-03-27 2003-10-02 Shionogi & Co., Ltd. Decomposition inhibitor for extracellular matrix of cartilage
US20050227994A1 (en) 2002-03-27 2005-10-13 Shionogi & Co., Ltd. Decomposition inhibitor for extracellular matrix of cartilage
JP2005539016A (en) 2002-08-02 2005-12-22 シエーリング アクチエンゲゼルシャフト Progesterone receptor modulators with enhanced anti-gonadotropin activity for female fertility regulation and hormone replacement therapy
WO2004014935A1 (en) 2002-08-02 2004-02-19 Schering Aktiengesellschaft Progesterone receptor modulators having an increased antigonadotropic activity for use in female fertility testing and hormone replacement therapy
WO2006121097A1 (en) 2005-05-12 2006-11-16 Astellas Pharma Inc. Bicyclic heterocyclic derivative or salt thereof
WO2007014927A2 (en) 2005-07-29 2007-02-08 Tibotec Pharmaceuticals Ltd. Macrocyclic inhibitors of hepatitis c virus
WO2007031349A1 (en) 2005-09-14 2007-03-22 Cosmo Bio-Technologies Srl Use of c3-c10 17alfa-esters of 9,11-dehydrocortexolone as anti-gonadotrophic agents.

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
Annen, K., et al., "17-Pivalate in der Pregnanreihe," Liebigs Ann. Chem:705-711, Wiley-VCH Verlag GmbH & Co. KGaA, Germany (1983).
Baldessari et al., "86. Lipase-Catalysed Regioselective Deacetylation of Androstane Derivatives," Helvetica Chimica Acta 79 (1996).
Belieu, R.M., "Mastodynia," Obstetrics and Gynecology Clinics of North America 21(3):461-477, W.B. Saunders Company, United States (1994).
Biollaz, von M. and Kalvoda, J., "263. Reaktionen von Steroiden mit Dialkylaminoschwefeltrifluoriden. I. 11beta-Hydroxysteroide." Helvetica Chimica Acta 60(8):2703-2710, Schweizerische Chemische Gesellschaft, Switzerland (1977).
Biollaz, von M. and Kalvoda, J., "263. Reaktionen von Steroiden mit Dialkylaminoschwefeltrifluoriden. I. 11β-Hydroxysteroide." Helvetica Chimica Acta 60(8):2703-2710, Schweizerische Chemische Gesellschaft, Switzerland (1977).
Bruttomesso, et al., "Lipase-catalysed deacetylation of androstane and pregnane dcrirativcs: influence of ring D substitution," Journal of Molecular Catalysis B: Ensymatic 29:149-153 (2004).
Byrn, S., et al., "Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations," Pharmaceutical Research 12(7):945-954, Plenum Publishing Company, United States (1995).
Caira, M.R., "Crystalline Polymorphism of Organic Compounds," in Topics in Current Chemistry, vol. 198, de Meijere, A., et al., Eds., pp. 164-208, Springer-Verlag, Germany (1998).
Celasco, et al., "Biological Profile of Cortexolone 17mu-Propionate (CB-03-01), a New Topical and Peripherally Selective Androgen Antagonist," Arzneim. Forsch./ Drug Res 54(12):881-886 (2004).
Celasco, et al., "Biological Profile of Cortexolone 17μ-Propionate (CB-03-01), a New Topical and Peripherally Selective Androgen Antagonist," Arzneim. Forsch./ Drug Res 54(12):881-886 (2004).
Cheung, et al., "Resistance to enzymic hydrolysis as a parameter in drug potency," International Journal of Pharmaceuticals 27:325-333 (1985).
Ferraboschi, et al., "Lipase-catalyzed preparation of corticosteroid 17mu-esters endowed with antiandrogenic activity," Tetrahedron Letters 49:4610-4612 (2008).
Ferraboschi, et al., "Lipase-catalyzed preparation of corticosteroid 17μ-esters endowed with antiandrogenic activity," Tetrahedron Letters 49:4610-4612 (2008).
Final Office Action, mailed Apr. 13, 2007 for U.S. Appl. No. 10/486,386, filed Sep. 16, 2004.
Final Office Action, mailed Feb. 27, 2009 for U.S. Appl. No. 10/486,386, filed Sep. 16, 2004.
Final Office Action, mailed Mar. 21, 2008 for U.S. Appl. No. 10/486,386, filed Sep. 16, 2004.
Ford, J.L. and Timmins, P., Eds., "Ch. 6 Thermal analysis in the characterization of pharmaceutical solids," in Pharmaceutical Thermal Analysis: Techniques and Applications, pp. 139-140, Ellis Horwood Limited, England (1989).
Franssen, et al., "Enzymatic alcoholysis of alkoxymethyl alkanoates: a possibile approach for the kinetic resolution of tertiary alcohols," Tetrahedron Letters 39:8345-8348 (2004).
Gardi, R., et al., "52. Derivati di condensazione nella catena laterale di corticosteroidi.-Nota III. Preparazione e reazioni dei 17-monesteri," Gazz. Chim. It. 93:431-450, Palermo, Italy (1963).
Gardi, R., et al., "Corticosteroid 17alpha-Monoesters from 17alpha,21-Cyclic Orthoesters," Tetrahedron Letters 13:448-451, Pergamon Press Ltd., Great Britain (1961).
Gardi, R., et al., "Corticosteroid 17α-Monoesters from 17α,21-Cyclic Orthoesters," Tetrahedron Letters 13:448-451, Pergamon Press Ltd., Great Britain (1961).
Hilfiker, R., Ed., "Characterization of Polymorphic Systems Using Thermal Analysis," in Polymorphisms in the Pharmaceutical Industry, pp. 46-48, Wiley-VCH Verlag GmbH & Co. KGaA, Germany (2006).
Japanese Office Action for Application No. 2010-518628 dated Feb. 8, 2013.
Meriggiola, M.C. and Pelusi, G., "Advances in male hormonal contraception," Expert Opin. Invcstig. Drugs 15(4):389-397, Ashley Publications, England (2006).
Misaki, et al., "Enzymic hydrolysis of hydrocoristone diesters in skin," Yakuzaigaku No. 42(2), Abstract. Caplus Chemical Abstract Service Database Accession No., 1982:575-431.
Morrison, R.T. and Boyd, R.N., Eds., "Chap. 20 Functional Derivatives of Carboxylic Acids," in Organic Chemistry, Sixth Edition, pp. 764-766, Prentice-Hall, Inc., Englewood Cliffs, New Jersey, United States (1992).
Non-Final Office Action, mailed Apr. 24, 2014 for U.S. Appl. No. 14/103,707, filed Dec. 11, 2013.
Non-Final Office Action, mailed Jul. 10, 2008 for U.S. Appl. No. 10/486,386, filed Sep. 16, 2004.
Non-Final Office Action, mailed Jul. 13, 2011 for U.S. Appl. No. 12/457,870, filed Jun. 24, 2009.
Non-Final Office Action, mailed Sep. 25, 2006 for U.S. Appl. No. 10/486,386, filed Sep. 16, 2004.
Non-Final Office Action, mailed Sep. 7, 2007 for U.S. Appl. No. 10/486,386, filed Sep. 16, 2004.
Notice of Allowance, mailed Sep. 23, 2015 for U.S. Appl. No. 14/474,765, Ajani, M., et al., filed Sep. 2, 2014.
Schinzer, W.C., et al., "Characterization and Interconversion of Polymorphs of Premafloxacin, a New Quinolone Antibiotic," Journal of Pharmaceutical Sciences 86(12):1426-1431, American Chemical Society and American Pharmaceutical Association, United States (1997).
Tuladhar, M.D., et al., "Thermal behaviour and dissolution properties of phenylbutazone polymorphs," J. Pharm. Pharmcol. 35:208-214, Pharmaceutical Society of Great Britain, England (1983).
Turner, R.B., "Acylation of 17-Hydroxy-20-ketosteroids," J. Am. Chem. Soc. 75:3489-3492, American Chemical Society, United States (1953).
Voigt, W. and Hsia, S.L., "The Antiandrogenic Action of 4-Androsten-3-one-17beta-Carboxylic Acid and Its Methyl Ester on Hamster Flank Organ," Endocrinology 92(4):1216-1222, Endocrine Society, United States (1973).
Voigt, W. and Hsia, S.L., "The Antiandrogenic Action of 4-Androsten-3-one-17β-Carboxylic Acid and Its Methyl Ester on Hamster Flank Organ," Endocrinology 92(4):1216-1222, Endocrine Society, United States (1973).

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10159682B2 (en) 2007-08-03 2018-12-25 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US10166245B2 (en) 2007-08-03 2019-01-01 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US10716796B2 (en) 2007-08-03 2020-07-21 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US11207332B2 (en) 2007-08-03 2021-12-28 Cassiopea S.P.A. Enzymatic process for obtaining 17 α-monoesters of cortexolone and/or its 9,11-dehydroderivatives
US11938141B2 (en) 2007-08-03 2024-03-26 Cassiopea S.P.A. Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Also Published As

Publication number Publication date
AU2008285784B2 (en) 2014-06-26
CN103450304B (en) 2016-05-25
PT2503005E (en) 2015-12-09
EP2503004A1 (en) 2012-09-26
US20110092472A1 (en) 2011-04-21
PT2966175T (en) 2019-06-27
EP2173891B1 (en) 2014-02-12
AR111202A2 (en) 2019-06-12
US20160324873A1 (en) 2016-11-10
CN104861023B (en) 2017-04-12
NZ599437A (en) 2013-11-29
PL2966175T3 (en) 2019-11-29
ES2732326T3 (en) 2019-11-21
EP2503005A3 (en) 2012-10-03
NZ615953A (en) 2015-03-27
EP2503005A2 (en) 2012-09-26
SI2503004T1 (en) 2015-12-31
ES2462946T3 (en) 2014-05-26
JP6174645B2 (en) 2017-08-02
US10159682B2 (en) 2018-12-25
WO2009019138A2 (en) 2009-02-12
PL2173891T3 (en) 2014-07-31
TR201909129T4 (en) 2019-07-22
PT2173891E (en) 2014-05-19
NZ600767A (en) 2013-11-29
CA2871025C (en) 2016-05-24
US20160051566A1 (en) 2016-02-25
DK2503005T3 (en) 2015-11-16
MX363701B (en) 2019-03-29
EP3521298A1 (en) 2019-08-07
RU2012113839A (en) 2013-10-20
RS53310B (en) 2014-10-31
KR20100044845A (en) 2010-04-30
MX2010001256A (en) 2010-05-17
US11207332B2 (en) 2021-12-28
US11938141B2 (en) 2024-03-26
EP2173891A2 (en) 2010-04-14
ITMI20071616A1 (en) 2009-02-04
HRP20151174T1 (en) 2015-12-04
US20220280531A1 (en) 2022-09-08
US20140179654A1 (en) 2014-06-26
RS54354B1 (en) 2016-04-28
PT2503004E (en) 2015-12-09
LT2966175T (en) 2019-08-26
CN101743316B (en) 2013-09-04
CN103450304A (en) 2013-12-18
JP2013163683A (en) 2013-08-22
JP6108944B2 (en) 2017-04-05
US9486458B2 (en) 2016-11-08
PL2503004T3 (en) 2016-05-31
CN104861023A (en) 2015-08-26
DK2966175T3 (en) 2019-07-01
CA2871039C (en) 2017-11-28
EP2503005B1 (en) 2015-09-02
US10166245B2 (en) 2019-01-01
AR072235A1 (en) 2010-08-18
RS54361B1 (en) 2016-04-28
HRP20191143T1 (en) 2019-09-20
US20200155572A1 (en) 2020-05-21
HRP20140421T1 (en) 2014-06-06
CA2871039A1 (en) 2009-02-12
HUE026507T2 (en) 2016-06-28
US20230104965A1 (en) 2023-04-06
PL2503005T3 (en) 2016-05-31
BRPI0814163A2 (en) 2015-01-20
MX363238B (en) 2019-03-15
JP2010535173A (en) 2010-11-18
CA2871025A1 (en) 2009-02-12
HUE044237T2 (en) 2019-10-28
ES2551910T3 (en) 2015-11-24
KR101495192B1 (en) 2015-02-25
CN101743316A (en) 2010-06-16
SI2173891T1 (en) 2014-06-30
EP2966175B1 (en) 2019-05-08
WO2009019138A3 (en) 2009-10-15
RU2599452C2 (en) 2016-10-10
AR111351A2 (en) 2019-07-03
US8785427B2 (en) 2014-07-22
SI2966175T1 (en) 2019-08-30
RU2010107599A (en) 2011-09-10
CA2691445A1 (en) 2009-02-12
ZA201000587B (en) 2011-04-28
AU2008285784A1 (en) 2009-02-12
DK2503004T3 (en) 2015-11-02
CA2691445C (en) 2017-11-28
SI2503005T1 (en) 2015-12-31
US20160326210A1 (en) 2016-11-10
RS58950B1 (en) 2019-08-30
JP2016014045A (en) 2016-01-28
US10716796B2 (en) 2020-07-21
EP2966175A1 (en) 2016-01-13
ZA201100133B (en) 2014-03-26
US20190083511A1 (en) 2019-03-21
HUE026206T2 (en) 2016-05-30
DK2173891T3 (en) 2014-04-28
HRP20151298T1 (en) 2016-01-01
ES2554934T3 (en) 2015-12-28
MX2019003639A (en) 2019-06-17
JP5646992B2 (en) 2014-12-24
EP2503004B1 (en) 2015-09-02
RU2482190C2 (en) 2013-05-20

Similar Documents

Publication Publication Date Title
US11938141B2 (en) Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives
AU2014233577B2 (en) Enzymatic process for obtaining 17 alpha-monoesters of cortexolone and/or its 9,11-dehydroderivatives

Legal Events

Date Code Title Description
AS Assignment

Owner name: COSMO DERMATOS SRL., ITALY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:COSMO S.P.A.;REEL/FRAME:031883/0911

Effective date: 20131219

AS Assignment

Owner name: CASSIOPEA S.P.A., ITALY

Free format text: CHANGE OF NAME;ASSIGNOR:COSMO DERMATOS SRL;REEL/FRAME:036163/0294

Effective date: 20150414

STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction
AS Assignment

Owner name: COSMO S.P.A., ITALY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:AJANI, MAURO;MORO, LUIGI;REEL/FRAME:047455/0017

Effective date: 20100803

FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4

PTEF Application for a patent term extension

Free format text: PRODUCT NAME: WINLEVI (CLASCOTERONE); REQUESTED FOR 909 DAYS

Filing date: 20201019

Expiry date: 20290228

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 8

AS Assignment

Owner name: CASSIOPEA S.P.A., ITALY

Free format text: CHANGE OF ADDRESS;ASSIGNOR:CASSIOPEA S.P.A.;REEL/FRAME:068999/0249

Effective date: 20240916